tbuckley/cabot-search huggingface dataset:
Oxaliplatin based chemotherapy for advanced well-differentiated neuroendocrine tumors: A systematic review and meta-analysis.
Authors: Jian Wang, Xiangling Wang, Yunxia Chu, Shuguang Li, Jing Hao
Journal: Journal of Clinical Oncology (2023)

e16240 Background: Currently, chemotherapy is predominantly considered in advanced well-differentiated neuroendocrine tumors (NENs) with high ki67 proliferation index and tumor burden. So far, no standard regimen is available and alkylating agents alone, such as temozolomide or in combination with 5-fluorouracil or capecitabine are widely used. Besides, oxaliplatin based chemotherapy has shown promising antitumor activity without being influenced by the MGMT status. In the current SRMA, we aim to address the efficacy of oxaliplatin based chemotherapy in advanced well differentiated NENs. Methods: We conducted a systematic database search using PubMed/MEDLINE and EMBASE. Eligible studies included randomized and single-arm trials, prospective observational and retrospective studies documenting the clinical efficacy of oxaliplatin based chemotherapy for advanced well-differentiated NENs. The pooled overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were calculated and weighted using generic inverse variance in a random-effects model, as well as subgroup analysis for pts with pancreatic NETs (pNETs) and extra-pancreatic NETs (epNETs), G1-2 and G3 NETs. Results: 14 of 24 identified publications were included with a combined total of 865 patients in 3 phase II trial and 11 retrospective studies. 495 pts received FOLFOX, 155 pts XELOX, 130 pts GEMOX and 138 pts plus bevacizumab. 48.4% (419/865) patients were pNETs, and G3 NETs accounted for 21.7% (188/865). The pooled ORR was 27.9% (237/865, 95% CI: 23.2-32.5). pNETs showed much higher ORRs (37.7%,114/303, 95% CI: 31.1-44.3) than epNETs (14.9%, 40/251, 95% CI: 10.5-19.2), χ2 = 32.17, p &lt; 0.001. ORRs in G1-2 NETs was 23.1% (66/273, 95% CI: 18.2-28.1), while in G3 NETs was 45.7% (42/85, 95% CI: 29.7-61.6), χ2 = 19.60, p &lt; 0.001. FOLFOX plus bevacizumab showed a higher ORR (38.3%, 38/98, 95% CI: 28.8-47.9) than the oxaliplatin based regimens without bevacizumab (26.9%, 166/594, 95% CI: 23.4-30.4), χ2 = 4.745, p = 0.029. The median PFS in pNETs was 8.1 months (n = 247, 95% CI: 6.3-9.9), similar to 8.4 months in epNETs (n = 211, 95% CI 5.7-11.2). The median PFS in G1-G2 and G3 NET was 13.4 months (95% CI 9.1-17.6) and 7.1 months (95% CI 4.1-9.6) respectively. Besides, FOLFOX plus bevacizumab also showed a trend of a longer PFS (12.4months, 95% CI 9.5-15.2) than those without bevacizumab (7.6months, 95% CI 6.8-8.3). The pooled median overall survival was 28.8months (95% CI 26.7-30.9). Conclusions: Among the advanced well-differentiated neuroendocrine tumors, oxaliplatin based chemotherapy alone or plus bevacizumab could be a good alternative regimen, especially in pts with pNETs and G3 NETs.
Real-world efficacy and safety data of anti-PD-1 plus anti-CTLA-4 combination therapy in Chinese patients with advanced melanoma.
Authors: Xizhi Wen, Xiaoshi Zhang, Ya Ding, Dandan Li, Jingjing Li
Journal: Journal of Clinical Oncology (2023)

e21530 Background: Combination of anti-PD-1 plus anti-CTLA-4 has shown superior efficacy over monotherapy in advanced melanoma among Caucasian populations. However, it has not been evaluated in Chinese patients, and data on acral and mucosal melanoma are limited. We aimed to assess the efficacy and safety of anti-PD-1 antibody plus ipilimumab therapy in Chinese patients with advanced melanoma in clinical practice. Methods: Advanced melanoma patients treated with anti-PD-1 antibody combined with ipilimumab in Sun-Yat sen University Cancer Center from May 2015 to October 2022 were retrospectively assessed. Patient baseline characteristics, tumor responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity was assessed to estimate safety. Results: Altogether, 86 patients were included. The primary site was cutaneous, acral, mucosal, uveal and central nervous system (CNS) in 34, 21, 20, six and five patients, respectively. Among them, 21 patients were treatment-naive, 65 patients were previously treated, and 54 patients progressed of front-line ani-PD-1 therapy. 12 patients received ipilimumab 3mg/kg combined with low dose anti-PD-1 (Nivolumab 80mg or Pembrolizumab 1mg/kg) Q3w for four doses, and the other 74 patients received standard dose of anti-PD-1 plus ipilimumab 1mg/kg Q3w therapy. There were 25(29%) patients with liver metastasis and 26(30.2%) patients with CNS metastasis at baseline. The overall response rate (ORR) was 15.1% in the whole cohort, with complete response observed in six (6%) patients, partial response in 7 (8.1%), stable disease in 28 (32.6%). The response rate in the treatment-naive and prior systemic therapy group was 23.8% and 12.3%, respectively. For those treated with anti-PD-1 followed by the anti-PD-1+ ipilimumab as subsequent therapy after disease progression, the ORR was 11.1%. The response rate for cutaneous melanoma was 23.5%, and 37.5% in the naïve group. Response rates for acral, uveal, CNS and mucosal melanoma were 19.0%, 16.7%,0% and 0% respectively. The median progression-free survival (PFS) and overall survival (OS) in all patients was 4.5 (3.6-5.4) months and 22.0 (12.4-31.6) months, respectively. The 3-year OS were 100% in patients who achieved ORR. There were no significant differences in PFS or OS for patients with cutaneous or acral melanoma. mucosal primary tumor type, liver metastasis and elevated LDH were predictive of shorter PFS and OS. CNS metastasis, previous treatment, BRAF/NRAS mutation status and sex were not found to be related to survival. Adverse events occurred in 71% of patients and 13% were grade 3 or worse. Conclusions: The efficacy of anti-PD-1+ ipilimumab combination therapy in Chinese patients tended to be inferior compared to global studies but was well tolerated. OS were good in cases with CR or PR.
IMM27M, a humanized Fc-engineered anti CTLA-4 antibody, in patients with advanced solid tumors: A phase I dose-escalation study.
Authors: Shusen Wang, Qingyuan Zhang, Quanli Gao, Shikai Wu, Enxiao Li, Zhi-hua Li, Ziquan Liu, Xiwen Zhao, Siman Gao, Qiying Lu, Wenzhi Tian
Journal: Journal of Clinical Oncology (2023)

e14670 Background: IMM27M is a humanized Fc-engineered IgG1 CTLA-4 monoclonal antibody with enhanced ADCC. In pre-clinical models, IMM27M could enhance immune responses and promote Treg depletion. The pre-clinical results showed IMM27M induced a significantly stronger anti-tumor activity than ipilimumab and resulted in complete tumor remission even at a low dose. Methods: This study is an open-label, multi-center, phase I dose-escalation study conducted to evaluate the safety, tolerability, maximum tolerated dose/recommended dose for expansion, PK and anti-tumor activity in patients with advanced solid tumors. The study was designed with an accelerated titration followed by a standard 3+3 design. IMM27M (0.1,0.3,1,2,3 mg/kg) was administered as monotherapy on Day 1 of every 3 weeks. Results: As of 30 Dec 2022, the dose has been escalated to 2mg/kg. 11 pts (8 female, 3 male) were enrolled and treated (1 at 0.1 mg/kg, 3 at 0.3 mg/kg, 3 at 1.0 mg/kg, 4 at 2.0 mg/kg), including 3 pts with melanoma, 3 pts with breast carcinoma, 2 pts with RCC, 1 pt with HCC, 1pt with NSCLC and 1 pt with ovarian carcinoma. Median age was 52 years (range 36-72). 9 pts (81.8%) received ≥ 2 lines of previous systemic therapies and 7 pts (63.6%) received previous anti PD-1/PD-L1 treatment. Treatment-related adverse events (TRAEs) occurred in 10 pts (90.9%) to date. Most TRAEs were grade 1 or 2. The most common TRAEs (≥ 10%) of all grades were anaemia (n = 3 [27.3%]), white blood cell count decreased (n = 2 [18.2%]), lymphocyte count decreased (n = 2 [18.2%]), constipation (n = 2 [18.2%]) and rash (n = 2 [18.2%]). Grade ≥3 TRAEs occurred in 2 pts (18.2%): lymphocyte count decreased (G3, n = 1 [9.1%]) and immune-related lung disease (G3, n = 1 [9.1%]). Treatment related SAE patients only occurred in 1 pt (immune-related lung disease, possibly related to treatment), and this patient recovered after clinical treatment. No DLT was observed. No TRAE leading to treatment discontinuation was reported. In 10 response evaluable pts, 3 pts had SD as best response. One pt in 2.0 mg/kg dose cohort had tumor shrinkage of 17% at Week 6, who had metastatic melanoma and received 2 lines of previous treatments including anti PD-1. The treatment of this patient is ongoing. Preliminary PK analysis of IMM27 showed an approximate proportional dose curve and the mean t 1/2 was around 11 days. Conclusions: IMM27M monotherapy in general was well-tolerated at the dose level evaluated and preliminarily anti-tumor activity in patients with advanced solid tumors. The dose escalation study of IMM27M in advanced solid tumors is ongoing. Clinical trial information: NCT05235438 .
A phase I trial of diphencyprone for cutaneous neurofibromas in adult patients with neurofibromatosis type 1.
Authors: Dina Poplausky, Jade N Young, Brandon Block, Patricia Cabral, Ryan Rivera-Oyola, Yeriel Estrada, Giselle K Singer, Vicky K. Wong, Joel Correa Da Rosa, Rebecca M Brown, Nicholas Gulati
Journal: Journal of Clinical Oncology (2023)

TPS2678 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic tumor predisposition syndrome affecting about 1 in 2500 people. Affected patients develop a variety of skin findings including café-au-lait macules, axillary freckling, and cutaneous neurofibromas (cNFs). These patients also have an increased risk of malignant tumors including gliomas and soft tissue sarcomas. However, the cNFs, of which a patient can have thousands, are often cited as the most burdensome sign. Despite their benign nature, these tumors can be physically bothersome and cause significant emotional distress. To date, there are no effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten that induces a delayed-type hypersensitivity skin reaction, for the treatment of cNFs in adults with NF1. Methods: This trial is enrolling NF1 patients aged 18 and older with at least four cNFs greater than 4mm. Subjects taking systemic immunosuppressants, those with underlying immunodeficiency or uncontrolled intercurrent illnesses, and those who are pregnant or nursing are excluded from the study. DPCP 0.04% ointment is administered topically once weekly to up to 20 cNFs in a localized area for 10 weeks. The primary endpoint is to determine the safety and tolerability of DPCP ointment in the treatment of cNFs. Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. To assess subjective tolerability, subjects score their symptoms, including pain, stinging, burning, and pruritus from 0 (none) to 3 (severe). Efficacy and tumor regression are assessed using the Response Evaluation Criteria in Solid Tumors guidelines in conjunction with photographs and manual tri-axial tumor measurements. Additionally, qualitative assessments are made by the study team using 3D whole-body photography. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a cNF and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints. Quantitative RT-PCR and single-cell RNA sequencing studies will assess gene expression changes in immune and tumor cell-related genes pre- and post-treatment with DPCP. Immunohistochemistry and proteomic profiling will be performed to characterize changes in the tumor microenvironment. Genetic testing for the NF1 germline mutation will be correlated with treatment response. Enrollment is ongoing with a target of 20 participants. Since September 2022, the study has enrolled 12 patients and five have completed the study. Clinical trial information: NCT05438290 .
Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.
Authors: Prantesh Jain, Alan Hutson, Cayla Janes, Debora S. Bruno, Greg Andrew Durm, Ashish Sangal, Bhoomi Mehrotra, Tania Crombet Ramos, Kalet Leon, Grace K. Dy
Journal: Journal of Clinical Oncology (2023)

TPS2677 Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 &gt; 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 &lt; 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression &lt;50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .
Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors.
Authors: Ye Guo, Jun Guo, Ying Cheng, Zhen Wang, Yongsheng Li, Dongqing Lv, Yongmei Yin, Guiling Li, Lingying Wu, Yi Huang, Shuqing Wei, Lin Shen, Huaxin Duan, Jiuwei Cui, Hong Luo, Xiumin Li, Kejun Nan, Chunyan Wang, Su-xia Luo, Ruonan Liu
Journal: Journal of Clinical Oncology (2023)

2536 Background: PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. We had completed dose escalation from 1mg/kg to 45mg/kg and had not found DLT/MTD. In a Phase Ib dose expansion and Phase IIa studies we are evaluating the safety and preliminary anti-tumor activity of PM8002 as a monotherapy. Here, we provide an update of PM8002 Phase Ib/IIa results. Methods: During Phase Ib dose-expansion and Phase IIa studies, the majority of patients received PM8002 at 20mg/kg Q2W or 30mg/kg Q3W as a monotherapy (recommended phase II doses). The primary endpoint was ORR with secondary endpoints/objectives including safety. Results: As of Feb 3, 2023, 263 patients of advanced solid tumor with prior 0 to 4 line systematic treatment had been enrolled (1mg/kg Q2W [n=1], 10mg/kg Q2W [n =1], 20mg/kg Q2W [n=190], 20mg/kg Q3W [n=4], 30mg/kg Q2W [n=4], 30mg/kg Q3W [n=52], and 45mg/kg Q3W [n=11]). The median duration of exposure was 10.6 weeks (range, 0.1—51.0). Of the 263 enrolled patients, 211 had completed their first evaluation for efficacy. The overall ORR, regardless of tumor type, was 15.2% (32/211) with 32 PRs (20 confirmed PRs), and the DCR was 75.4% (159/211) per RECIST 1.1. Twenty-five patients with cervical cancer had an ORR of 28% (7/25). Twenty-six patients with renal cell carcinoma had an ORR of 26.9% (7/26). Twenty-six patients with platinum-resistant ovarian cancer had an ORR of 15.4% (4/26), and 27 patients with NSCLC (with EGFR mutations) had an ORR of 18.5% (5/27). Any-grade TRAEs occurred in 68.8% patients (181/263), with 18.3% Grade ≥3 (48/263). The most common TRAEs were proteinuria (17.5%), hypertriglyceridemia (11.4%), Aspartate aminotransferase (9.9%), Alanine aminotransferase increased (9.5%), Hypoalbuminemia (8.7%), and increased gamma-glutamyl transferase levels (6.8%). Thirty-six patients (13.7%) discontinued PM8002 due to TRAEs. No death-related cases occurred, and most patients remain on treatment. Conclusions: PM8002 showed encouraging antitumor activity and good safety in patients with advanced solid tumors. Phase 1b/IIa of PM8002 as a monotherapy and Phase II combination trials of PM8002 with chemotherapy are ongoing for multiple indications. Clinical trial information: ChiCTR2000040552.
SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.
Authors: Mark Andrew Dickson, Karla V. Ballman, Mia C. Weiss, Steven Attia, Michael J Wagner, Seth Pollack, Edwin Choy, Andrew J. Wagner, Breelyn A. Wilky, Lara E. Davis, Richard F. Riedel, William D. Tap
Journal: Journal of Clinical Oncology (2023)

TPS11587 Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .
A phase 2 single-arm study of berzosertib in combination with irinotecan in patients with progressive TP53 mutant gastric and gastro-esophageal junction cancer.
Authors: Shannon Stockton, Heloisa P. Soares, Farshid Dayyani, Anwaar Saeed, Edward S. Kim, Ning Jin, George Hosni Yacoub, Jennifer Whisenant, G. Dan Ayers, Steven Gore, Satya (Nanu) Das, Jordan Berlin
Journal: Journal of Clinical Oncology (2023)

4044 Background: TP53 mutations are reported in 30-70% of patients with metastatic/unresectable gastric (G) and gastro-esophageal junction (GEJ) adenocarcinoma and are associated with a poor prognosis. Novel therapeutics are needed. Gastrointestinal cancer cell lines with TP53 mutations demonstrate reliance on the ataxia telangiectasia and Rad3-related protein kinase (ATR) axis for DNA damage repair (DDR) in vitro. The ATR axis is triggered by single-strand DNA breaks and thus combining ATR inhibitors with topoisomerase I (TopI) inhibitors may have a synergistic effect, particularly in patients with TP53 mutant tumors. Irinotecan, a TopI inhibitor, is an established cytotoxic therapy for gastric and GEJ adenocarcinoma. We evaluated irinotecan in combination with the ATR inhibitor berzosertib (formerly M6620) in patients with TP53-mutated gastric and GEJ adenocarcinoma. Methods: This was a single-arm phase II study in third-line patients with G/GEJ cancers possessing TP53 mutations (exon 2 and exons 4-11). Patients received irinotecan 180 mg/m 2 IV and berzosertib 270 mg/m 2 IV on days 1 and 15 every 28 days. The primary endpoint was overall response rate (ORR) (Ha: 35% and Ho:15%). A subset of patients underwent biopsies on C1D1 post-irinotecan and C2D2 to evaluate the expression of DDR biomarkers Y-H2AX, KAP1 p-Ser 824, and p-ATR. Results: A total of 17 patients were enrolled. Of 16 efficacy-evaluable patients, one experienced a partial response. The ORR was 6.2% thus the primary endpoint was not met. The disease control rate was 56.2%. Median progression-free survival was 4.01 months [95% CI 2.07-Not Reached]. Median overall survival was 6.21 months [95% CI 4.83-8.61]. No new safety signals were observed with the experimental treatment combination and the most common ≥ grade 3/4 treatment-related adverse events were neutropenia (4/17, 23.5% patients), anemia (3/17, 17.6%), febrile neutropenia (2/17, 11.8%), and diarrhea (2/17, 11.8%). No grade 5 events occurred. Conclusions: Although the primary endpoint of ORR was not met, the combination of irinotecan and berzosertib in patients with TP53-mutated G/GEJ adenocarcinoma was well-tolerated and demonstrated anti-tumor activity comparable to other agents with published later-line data (e.g. ramucirumab+paclitaxel, TAS-102). Analyses of pharmacodynamic biomarkers of DNA damage repair are in process. While further clinical development of berzosertib is not planned, other ATR inhibitors are being explored in combination with irinotecan in gastrointestinal malignancies, including G/GEJ cancer. Clinical trial information: NCT03641313 . [Table: see text]